Alan H. Bryce, MD, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discusses the accelerated approval of rucaparib (Rubraca) for the treatment of adult patients with 

 mutation (germline and/or somatic)—associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.

The accelerated approval is based on findings from the ongoing phase 2 TRITON2 trial (NCT02952534), in which the PARP inhibitor demonstrated a 44% confirmed objective response rate (ORR) in 62 evaluable patients with 

The results of the TRITON2 trial confirm historical data showing the efficacy of PARP inhibitors in 

-mutant prostate cancer, says Bryce. The regulatory decision marks the first approval for a biomarker-driven targeted therapy in prostate cancer, says Bryce. With this approval, patients with 

-mutant mCRPC now have access to an extremely effective and attractive treatment option, concludes Bryce.

Videos

Alan H. Bryce, MD, discusses the accelerated approval of rucaparib (Rubraca) for the treatment of adult patients with BRCA mutation (germline and/or somatic)–associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.

Dr. Bryce on the FDA Approval of Rucaparib in BRCA-Mutant mCRPC

Alan H. Bryce, MD, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discusses ongoing research regarding 

-altered prostate cancer accounts for 5% to 10% of all prostate cancers, says Bryce. Patients with a 

 mutation have a poor response to traditional antiandrogen agents such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), and PARP inhibitors. However, these patients appear to respond well to immunotherapy.

CDK12 appears to regulate chromosomal stability, says Bryce. As such, a 

 mutation can lead to large tandem duplications and chromosomal rearrangements, which increases neoantigen production.

In a retrospective, multicenter analysis of 58 men with monoallelic 

 alterations, 8 patients with metastatic castration-resistant prostate cancer had been treated with a PD-1 inhibitor. Among these patients, 38% had a prostate specific antigen

) response, explains Bryce. Additionally, none of the 11 patients treated with a PARP inhibitor had a PSA

With further research, CDK12 could become a biomarker of response to checkpoint inhibitors in prostate cancer, concludes Bryce.

Alan H. Bryce, MD, discusses ongoing research regarding CDK12 alterations in prostate cancer.

Dr. Bryce on Ongoing Research Regarding CDK12 Alterations in Prostate Cancer

Alan H. Bryce, MD, assistant professor of medicine and medical director of the Genomic Oncology Clinic, Mayo Clinic, discusses ongoing research in prostate cancer.

The ongoing phase III AFT19 trial is evaluating apalutamide (Erleada) in patients with biochemically relapsed disease. In the 3-arm study, patients will be randomized to receive either androgen deprivation therapy (ADT) alone, ADT plus apalutamide, or ADT, apalutamide, and abiraterone acetate (Zytiga).

Similar to the phase III CHAARTED and STAMPEDE studies, AFT19 is trying to take effective agents and bring them into earlier-line settings, which could potentially translate to significant improvements in overall survival, explains Bryce.

In addition, more studies taking approved agents in metastatic castration-resistant disease and moving them into the hormone-sensitive and nonmetastatic setting are expected, concludes Bryce.

Dr. Bryce on Ongoing Research in Prostate Cancer

Alan H. Bryce, MD, assistant professor of medicine, Mayo Clinic, discusses the use of next-generation radiopharmaceuticals in prostate cancer.

A study with lutetium-177, which is attached to prostate-specific membrane antigen (PSMA), has recently completed accrual, says Bryce. In prostate cancer, PSMA receptors are overexpressed on the surface of cancer cells. As such, when lutetium-177 is combined with PSMA, the radioactive isotope is easily delivered to malignant cells. Unlike radium-223, PSMA-targeting is delivered equally in bone, soft tissue, and other locations of metastasis within the body, explains Bryce. Once the PSMA delivers the radiation to the prostate cancer cell, the lutetium radiation decays around the cancer cell.

The treatment strategy was originally developed in Germany and then was tested in Australia, says Bryce. Encouraging signals of activity were reported in preliminary single-arm studies. As such, Bryce is hopeful that the phase III study could show similar findings.

Dr. Bryce on Next-Generation Radiopharmaceuticals in Prostate Cancer

Alan H. Bryce, MD, assistant professor of medicine, Mayo Clinic, discusses potential biomarkers of response to immunotherapy in prostate cancer.

Checkpoint inhibitors have shown limited success in prostate cancer, which could be due, in part, to poor patient selection. For example, patients with high microsatellite instability (MSI-H) benefit from immunotherapy. However, only 2% to 3% of patients with prostate cancer are MSI-H.

Data presented at the 2019 ESMO Congress suggest that CDK12 could be a predictor of response to checkpoint inhibition in prostate cancer. When a somatic 

 mutation is present in a prostate cancer cell, it leads to genomic instability and a high rate of large tandem exon duplications as well as chromosomal rearrangements, explains Bryce. Tumor mutational burden (TMB) has been investigated as another biomarker of response to immunotherapy. However, in prostate cancer, TMB-high is 4 or 5 where generally, TMB-high is considered to be 10 mutations/megabase. Notably, TMB is considered to be a surrogate for neoantigens which could lead back to CDK12, adds Bryce.

In addition to checkpoint inhibitors, bispecific antibodies and CAR T-cell therapies are also under investigation, concludes Bryce.

Alan H. Bryce, MD, discusses potential biomarkers of response to immunotherapy in prostate cancer.

Dr. Bryce on Potential Biomarkers of Response to Immunotherapy in Prostate Cancer

Alan H. Bryce, MD, assistant professor of medicine, Mayo Clinic, discusses treatment selection in nonmetastatic castration-resistant prostate cancer (M0CRPC).

Enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) are approved for the treatment of patients with M0CRPC based on data from the phase III PROSPER, SPARTAN, and ARAMIS trials, respectively. The trials were designed similarly and they launched within a few years of each other, says Bryce. Although cross-trial comparisons are discouraged, the results from all 3 trials showed a similar benefit in metastasis-free survival ranging from 3 to 4 years with the antiandrogen versus the comparator.

However, the drugs do differ in their toxicity profiles and administration schedules, says Bryce. For example, darolutamide is given twice daily rather than once daily. Because there are no head-to-head data comparing these agents, it will be important for the field to gain experience in the clinic to learn which patients are going to do better with which agent, Bryce concludes.

Alan H. Bryce, MD, discusses treatment selection in nonmetastatic castration-resistant prostate cancer.

Dr. Bryce on Treatment Selection in Nonmetastatic Castration-Resistant Prostate Cancer

Alan H. Bryce, MD, assistant professor of medicine, Mayo Clinic, discusses the importance of individualized approaches in the use of abiraterone (Zytiga) versus docetaxel in patients with metastatic hormone-sensitive prostate cancer.

Both abiraterone and docetaxel are approved in the frontline setting for hormone-sensitive metastatic disease. There’s no easy answer as to whether patients should receive abiraterone or docetaxel; it’s very individualized to the patient. It depends on the patient’s disease state, disease burden, pace of disease, and the patient’s tolerability.

Data from the STAMPEDE study suggest that in the frontline setting, there is very little difference between the two agents in terms of overall survival. This was a secondary and underpowered analysis from the trial, so it’s not a definitive answer, says Bryce.

Docetaxel is more toxic in the short-term. Most patients tend to favor abiraterone because it is a milder agent. Researchers are now trying to define the subsets of patients who will do better on chemotherapy than on abiraterone.

Dr. Bryce on the Use of Abiraterone Versus Docetaxel in Patients With Prostate Cancer

Alan H. Bryce, MD, medical oncologist, Mayo Clinic, discusses the need for molecular testing in patients with metastatic or high-risk stage III melanoma.

There are various professional opinions on when molecular testing is appropriate for these patients, Bryce explains. However, by doing comprehensive sequencing of tumors at each stage, researchers are able to gather more knowledge on decreasing the risk of disease recurrence by defining who does not require treatment. It also increases benefit to patients by accelerating drug development.

From an economic perspective, Bryce explains that because molecular testing is expensive, patient selection is imperative.

Ultimately, Bryce says, clinicians should decide if molecular testing is necessary for a patient's situation and how high his/her risk is of disease recurrence. Frequently, both clinicians and patients will decide that molecular testing is needed, he says.